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Development of colonic and pancreatic endocrine tumours in mice expressing a glucagon-SV40 T antigen transgene

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Abstract

We report the histological, immunohistochemical and ultrastructural changes in mice containing a chimeric glucagon-simian virus 40 T antigen (SV40Tag) gene. Transgene expression was detected in endocrine cells of pancreas, small and large intestine. Hyperplasia of glucagon-containing cells developed in pancreas and large bowel by gestational day 19. In large bowel, hyperplastic cells increased in number postnatally and invasive carcinomas were identified at 4 weeks; several animals had lymph node metastases. In contrast, no pathology was detected in the small bowel in any of the transgenic mice. Colonic tumours expressed SV40Tag, proglucagon-derived peptides and peptide YY (PYY); scattered cells contained cholecystokinin or glycoprotein hormone α-subunit. Somatostatin or serotonin was also detected in some tumours. By electron microscopy, the colonic tumours retained features of endocrine differentiation, but secretory granules were smaller than those of non-tumorous intestinal glucagon-producing L cells. In postnatal pancreas, atypical cells containing SV40Tag and glucagon were initially clustered at the periphery of islets; this atypical hyperplasia progressed to neoplasia by 11–12 weeks. Some neoplastic pancreatic cells contained glucagon, PYY or vasoactive intestinal peptide immunopositivity, but most were negative for all peptides; they contained immunoreactivity for tyrosine hydroxylase and by electron microscopy, pancreatic tumour cells had neuronal features. Pancreatic polypeptide was not detected in the non-tumorous islets of transgenic animals. This line of transgenic mice provides a model for the analysis of endocrine tumour progression in the gut and pancreas.

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References

  1. Ali-Rachedi A, Varndell IM, Adrian TE, Gapp DA, Noorden S van, Bloom SR, Polak JM (1984) Peptide YY (PYY) immunoreactivity is co-stored with glucagon-related immunoreactants in endocrine cells of the gut and pancreas. Histochemistry 80:487–491

    Google Scholar 

  2. Alpert S, Hanahan D, Teitelman G (1988) Hybrid insulin genes reveal a developmental lineage for pancreatic endocrine cells and imply a relationship with neurons. Cell 53:295–308

    Google Scholar 

  3. Astrin SM, Costanzi C (1989) The molecular genetics of colon cancer. Semin Diagn Pathol 16:138–147

    Google Scholar 

  4. Axelson J, Ekelund M, Sundler F, H»kanson R (1990) Enhanced hyperplasia of gastric enterochromaffinlike cells in response to omeprazole-evoked hypergastrinemia in rats with portacaval shunts. An immunocytochemical and chemical study. Gastroenterology 99:635–640

    Google Scholar 

  5. Bell RH Jr, Memoli VA, Longnecker DS (1990) Hyperplasia and tumors of the islets of Langerhans in mice bearing an elastase 1-SV40 T-antigen fusion gene. Carcinogenesis 11:1393–1398

    Google Scholar 

  6. Bosman FT (1989) Endocrine cells in non-endocrine tumours. J Pathol 159:181–182

    Google Scholar 

  7. Böttcher G, Sjölund K, Ekblad E, H»kanson R, Schwartz TW, Sundler F (1984) Coexistence of peptide YY and glicentin immunoreactivity in endocrine cells of the gut. Regul Pept 8:261–266

    Google Scholar 

  8. Böttcher G, Alumets J, J»kanson R, Sundler F (1986) Co-existence of glicentin and peptide YY in colorectal L-cells in cat and man. An electron microscopic study. Regul Pept 13:283–291

    Google Scholar 

  9. Brubaker PL, Drucker DJ, Asa SL, Greenberg GR (1991) Regulation of peptide-YY synthesis and secretion in fetal rat intestinal cultures. Endocrinology 129:3351–3358

    Google Scholar 

  10. Brubaker PL, Lee YC, Drucker DJ (1992) Alterations in proglucagon processing and inhibition of proglucagon gene expression in transgenic mice which contain a chimeric proglucagon-SV40 T antigen gene. J Biol Chem 267:20728–20733

    Google Scholar 

  11. Campos RV, Drucker DJ (1992) Transgenic mice in the study of endocrine systems. Endocr Pathol 3:111–115

    Google Scholar 

  12. Cheng H, Leblond CP (1974) Origin, differentation and renewal of the four main epithelial cell types in the mouse small intestine. V. Unitarian theory of the origin of the four epithelial cell types. Am J Anat 141:537–562

    Google Scholar 

  13. Cheng H, Leblond CP (1974) Origin, differentiation and renewal of the four main epithelial cell types in the mouse small intestine. III. Entero-endocrine cells. Am J Anat 141:503–520

    Google Scholar 

  14. Colony PC, Helmstaedter V, Moody AJ, Garaud JC, Forssmann WG (1982) Glucagon and glicentin immunoreactive cells in human colon. Cell Tissue Res 221:483–491

    Google Scholar 

  15. Drucker DJ, Asa SL (1988) Glucagon gene expression in vertebrate brain. J Biol Chem 263:13475–13478

    Google Scholar 

  16. Efrat S, Linde S, Kofod H, Spector D, Delannoy M, Grant S, Hanahan D, Baekkeskov S (1988) Beta-cell lines derived from transgenic mice expressing a hybrid insulin gene-oncogene. Proc Natl Acad Sci USA 85:9037–9041

    Google Scholar 

  17. Efrat S, Teitelman G, Anwar M, Ruggiero D, Hanahan D (1988) Glucagon gene regulatory region directs oncoprotein expression to neurons and pancreatic α cells. Neuron 1:605–613

    Google Scholar 

  18. Fiocca R, Capella C, Buffa R, Fontana R, Solcia E, Hage E, Chance RE, Moody AJ (1980) Glucagon-, glicentin-, and pancreatic polypeptide-like immunoreactivities in rectal carcinoids and related colorectal cells. Am J Pathol 100:81–92

    Google Scholar 

  19. Fiocca R, Rindi G, Capella C, Grimelius L, Polak JM, Schwartz TW, Yanaihara N, Solcia E (1987) Glucagon, glicentin, proglucagon, PYY, PP and proPP-icosapeptide immunoreactivities of rectal carcinoid tumors and related non-tumor cells. Regul Pept 17:9–29

    Google Scholar 

  20. Fujita T (1976) The gastro-enteric endocrine cell and its paraneuronic nature. In: Coupland RE, Fujita T (eds) Chromaffin, enterochromaffin and related cells. Elsevier, Amsterdam, pp 191–208

    Google Scholar 

  21. Garaud JC, Eloy R, Moody AJ, Stock C, Grenier JF (1980) Glucagon- and glicentin-immunoreactive cells in the human digestive tract. Cell Tissue Res 213:121–136

    Google Scholar 

  22. Grant SGN, Seidman I, Hanahan D, Bautch VL (1991) Early invasiveness characterizes metastatic carcinoid tumors in transgenic mice. Cancer Res 51:4917–4923

    Google Scholar 

  23. Hanahan D (1985) Heritable formation of pancreatic β-ell tumours in transgenic mice expressing recombinant insulin/simian virus 40 oncogenes. Nature 315:115–122

    Google Scholar 

  24. Hanahan D (1989) Transgenic mice as probes into complex systems. Science 246:1265–1275

    Google Scholar 

  25. Herrera P-L, Huarte J, Sanvito F, Meda P, Orci L, Vassalli J-D (1991) Embryogenesis of the murine endocrine pancreas; early expression of pancreatic polypeptide gene. Development 113:1257–1265

    Google Scholar 

  26. Hogan B, Constantini F, Lacy E (1986) Manipulating the mouse embryo: a laboratory manual. Cold Spring Harbor Laboratory, Cold Spring Harbor, NY

    Google Scholar 

  27. Jaenisch R (1988) Transgenic animals. Science 240:1468–1474

    Google Scholar 

  28. Kirkland SC (1988) Clonal origin of columnar, mucous, and endocrine cell lineages in human colorectal epithlium. Cancer 61:1359–1363

    Google Scholar 

  29. Larsson L-I (1977) Ontogeny of peptide-producing nerves and endocrine cells of the gastro-duodeno-pancreatic region. Histochemistry 54:133–142

    Google Scholar 

  30. Lee YC, Asa SL, Drucker DJ (1992) Glucagon gene 5'-flanking sequences direct expression of simian virus 40 large T antigen to the intestine, producing carcinoma of the large bowel in transgenic mice. J Biol Chem 267:10705–10708

    Google Scholar 

  31. Lewin KJ (1986) The endocrine cells of the gastrointestinal tract. The normal endocrine cells and their hyperplasias. Pathol Annu 21:1–27

    Google Scholar 

  32. Munger BL (1981) Morphological characterization of islet cell diversity. In: Cooperstein SJ, Watkins D (eds) The islets of Langerhans. Academic Press, New York, pp 3–34

    Google Scholar 

  33. Murphy D, Bishop A, Rindi G, Murphy MN, Stamp GWH, Hanson J, Polak JM, Hogan B (1987) Mice transgenic for a vasopressin-V40 hybrid oncogene develop tumors of the endocrine pancreas and the anterior pituitary: a possible model for human multiple endocrine neoplasia type 1. Am J Pathol 129:552–566

    Google Scholar 

  34. Nigro JM, Baker SJ, Preisinger AC, Jessup JM, Hostetter R, Cleary K, Bigner SH, Davidson N, Baylin S, Devilee P, Glover T, Collins FS, Weston A, Modali R, Harris CC, Vogelstein B (1989) Mutations in the p53 gene occur in diverse human tumour types. Nature 342:705–708

    Google Scholar 

  35. Nilsson O, Bilchik AJ, Goldenring JR, Ballantyne GH, Adrian TE, Modlin IM (1991) Distribution and immunocytochemical colocalization of peptide YY and enteroglucagon in endocrine cells of the rabbit colon. Endocrinology 129:139–148

    Google Scholar 

  36. Pearse AGE (1974) The APUD cell concept and its implications in pathology. Pathol Annu 9:27–41

    Google Scholar 

  37. Pearse AGE (1984) Islet development and the APUD concept. In: Klöppel G, Heitz PU (eds) Pancreatic pathology. Churchill Livingstone, Edinburgh, pp 125–132

    Google Scholar 

  38. Pictet RL, Rall LB, Phelps P, Rutter WJ (1976) The neural crest and the origin of the insulin-producing and other gastrointestinal hormone-producing cells. Science 191:191–192

    Google Scholar 

  39. Powers AC, Philippe J, Hermann H, Habener JF (1988) Sodium butyrate increases glucagon and insulin gene expression by recruiting immunocytochemically negative cells to produce hormone. Diabetes 37:1405–1410

    Google Scholar 

  40. Rindi G, Grant SGN, Yiangou Y, Ghatei MA, Bloom SR, Bautch VL, Solcia E, Polak JM (1990) Development of neuroendocrine tumors in the gastrointestinal tract of transgenic mice. Heterogeneity of hormone expression. Am J Pathol 136:1349–1363

    Google Scholar 

  41. Rindi G, Efrat S, Ghatei MA, Bloom SR, Solcia E, Polak JM (1991) Glucagonomas of transgenic mice express a wide range of general neuroendocrine markers and bioactive peptides. Virchows Arch [A] 419:115–129

    Google Scholar 

  42. Rindi G, Solcia E, Polak JM (1991) Peptide expression patterns in neuroendocrine tumors of transgenic mice. In: Fuxe K, Agnati LF (eds) Volume transmission in the brain: novel mechanisms for neural transmission. Raven Press, New York, pp 227–235

    Google Scholar 

  43. Rombout JHWM, Grinten CPM van der, Peeze Binkhorst FM, Taverne-Thiele JJ, Schooneveld H (1986) Immunocytochemical identification and localization of peptide hormones in the gastro-entero-pancreatic (GEP) endocrine system of the mouse and a stomachless fish, Barbus conchonius. Histochemistry 84:471–483

    Google Scholar 

  44. Roth KA, Gordon JI (1990) Spatial differentiation of the intestinal epithelium: analysis of enteroendocrine cells containing immunoreactive serotonin, secretin, and substance P in normal and transgenic mice. Proc Natl Acad Sci USA 87:6408–6412

    Google Scholar 

  45. Schweisthal MR, Frost CC, Brinn JE (1976) Ontogeny of four cell types in fetal rat islets using histochemical techniques. Acta Diabetol Lat 13:30–39

    Google Scholar 

  46. Teitelman G, Joh TH, Reis DJ (1981) Transformation of catecholaminergic precursors into glucagon (A) cells in mouse embryonic pancreas. Proc Natl Acad Sci USA 78:5225–5229

    Google Scholar 

  47. Teitelman G, Alpert S, Polak JM, Martinez A, Hanahan D (1993) Precursor cells of mouse endocrine pancreas coexpress insulin, glucagon and the neuronal proteins tyrosine hydroxylase and neuropeptide Y, but not pancreatic polypeptide. Development 118:1031–1039

    Google Scholar 

  48. Upchurch BH, Aponte GW, Leiter AB (1994) Expression of peptide YY in all four islet cell types in the developing mouse pancreas suggests a common peptide YY-producing progenitor. Development 120:245–252

    Google Scholar 

  49. Weinberg RA (1991) Tumor suppressor genes. Science 254:1138–1146

    Google Scholar 

  50. Wright NA (1990) Endocrine cells in non-endocrine tumours. J Pathol 161:85–87

    Google Scholar 

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Authors and Affiliations

  1. Department of Pathology, Mount Sinai Hospital and the University of Toronto, 600 University Avenue, M5G 1X5, Toronto, Ontario, Canada

    S. L. Asa

  2. The Banting and Best Diabetes Center, University of Toronto, Toronto, Ontario, Canada

    Y. C. Lee & D. J. Drucker

  3. Departments of Medicine, Clinical Biochemistry and Genetics, The Toronto Hospital, Toronto, Ontario, Canada

    D. J. Drucker

  4. Department of Physiology, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong

    Y. C. Lee

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  1. S. L. Asa
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  2. Y. C. Lee
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  3. D. J. Drucker
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Asa, S.L., Lee, Y.C. & Drucker, D.J. Development of colonic and pancreatic endocrine tumours in mice expressing a glucagon-SV40 T antigen transgene. Vichows Archiv A Pathol Anat 427, 595–606 (1996). https://doi.org/10.1007/BF00202891

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  • DOI: https://doi.org/10.1007/BF00202891

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